Catequentinib (anlotinib) in Sequential Combination with Immunotherapy for Use in the Treatment of Cancer

The present application is a continuation of International Patent Application No. PCT/US2020/021457, filed Mar. 6, 2020, which claims the benefit of priority to U.S. Provisional Patent Application No. 62/876,181, filed Jul. 19, 2019, and U.S. Provisional Patent Application No. 62/815,266, filed Mar. 7, 2019, the entirety of each of which is hereby incorporated by reference herein. Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57.

The present invention relates to a chemo combination therapy regimen to treat cancer. More specifically, the present invention relates to a novel chemo combination therapy regimen which relates to the combination of compound AL3818 (anlotinib, catequentinib) or its pharmaceutically acceptable salts with standard platinum-based and other chemotherapy agents or immunotherapy agents. The combination of these agents should be able to provide higher efficacy than employing any agent individually.

Currently, cancer is typically treated by one or a combination of methodologies, which include surgery, radiation therapy, chemotherapy and immunotherapy. In the past decades, rapid advances in chemotherapy were observed, which could provide much more possibility for reducing the mortality caused by cancer. Recent years, immunotherapy has gained enormous advancement in cancer therapy as well.

Paclitaxel is a well-known chemotherapy medication used to treat a number of types of cancer. The mechanism of action for paclitaxel is the paclitaxel could stabilize the microtubule polymer in the cells and protects them from disassembly. This function could block the mitosis process of cancer cells.

Carboplatin and cisplatin are both traditional platinum-based chemotherapeutic agents that used to treat various types of cancer. The mechanism of action for them is the platinum-based agents are able to form intra- or inter-linkage of DNA molecules in the cell. This manipulation can modify DNA structure and inhibits its synthesis, especially in cancer cells.

Protein tyrosine kinases (PTKs) are a series of enzymes that catalyze the phosphorylation of tyrosine residues in proteins. They play an important role in the cellular signal transduction cascades from extracellular signals through membrane to the cytoplasm and even nucleus. According to the different structures of the extracellular domains, they can be classified as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and so on. Lots of studies have revealed that normal cells usually show no activity or low activity of PTKs, whereas many cancer cells feature over expression of PTKs. Obviously, the unusual hyperactivity of PTKs is closely correlated with the tumor cell growth and angiogenesis. For this reason, interrupting or blocking the activity of PTKs could dramatically suppress the growth of tumor cells. As a result, seeking for a PTK inhibitor with improved efficacy and safety profile has become an important target for designing and developing potential new anticancer drugs.

AL3818 (anlotinib, INN: catequentinib) is a novel multi-target receptor tyrosine kinase inhibitor. Study results have demonstrated that the compound AL3818 could inhibit the activities of tyrosine kinases such as vascular endothelial growth factor receptor (VEGFR1, VEGFR2/KDR, and VEGFR3). It has also demonstrated to be a strong inhibitor of fibroblast growth factor receptor (FGFR1, FGFR2, and FGFR3), platelet-derived growth factor receptor (PDGFR-a) and even the stem cell factor receptor (c-KIT) as well. This strong combination inhibition capability makes AL3818 (anlotinib) as a good candidate for multi-target kinase inhibitor that has the potential to express higher efficacy and less toxic than any other competitive products already been approved or still in development (see Shen et al. Journal of Hematology & Oncology 2018 11:120).

U.S. Pat. No. 8,148,532 disclosed the compound AL3818 and U.S. Pat. No. 2019000243 disclosed a mouse model of combining chemotherapy agents with AL3818 to show synergistic anti-tumor effects.

The present invention describes a combination therapy regimen, which based on the sequential administration of standard platinum-based chemotherapy (or immunotherapy) and compound AL3818 or its pharmaceutical acceptable salts. This action is trying to use compound AL3818 or its pharmaceutical acceptable salts to inhibit the activities of protein tyrosine kinases (PTKs), thereby to inhibit the angiogenesis, which is closely related to the development, invasion, and metastasis of tumors.

The present invention provides a regimen method to treat cancer in a subject in need thereof comprising: a standard platinum-based chemotherapeutic agent and another chemotherapeutic agent; or each individually; or an immunotherapeutic agent; in combing with AL3818 or its pharmaceutically acceptable salts in repeated cycles with the option of administration of maintenance mono therapy of AL3818 or its pharmaceutically acceptable salts.

More specifically, this present invention provides a chemo or immuno combination therapy regimen that used for treating cancer in human.

Accordingly, this chemo or immuno combination therapy regimen is administering to a subject in need thereof a chemotherapeutic or immunotherapy agent altogether with a kind of tyrosine kinase inhibitor.

In some embodiments, the chemotherapeutic or immunotherapy agent and tyrosine kinase inhibitor are administered cyclically in sequence.

The administration one cycle of the chemotherapeutic or immunotherapy agent can range from 2 to 6 weeks (eg. 3 weeks, 4 weeks, 5 weeks and 6 weeks). In the presented chemo combination therapy regimen, the chemotherapeutic or immunotherapy agent is administered periodically on a 3 weeks cycle (21-day cycle) at once a cycle, or 4 weeks (28-day cycle) at once or twice a cycle. In the presented combination therapy regimen, the chemotherapeutic or immunotherapy agent is preferably administered on a 3 weeks cycle (21-day cycle) at once per cycle.

The administration cycle of tyrosine kinase inhibitor can range from 1 to 4 weeks. In the presented chemo combination therapy regimen, the tyrosine kinase inhibitor is preferably administered periodically on a 3 weeks cycle (21-day cycle).

The described 21-day cycles include administration periods and therapy free periods. The chemotherapy or immunotherapy agent is administrated to the subject on the first day (Day 1) of the 21-day cycle. The tyrosine kinase inhibitor is administrated from Day 1-21 once or twice a day. The tyrosine kinase inhibitor is preferably administrated to the subject once daily for two weeks from Day 1 to Day 14 or Day 8 to Day 21 to have 7 days (Day 15 to Day 21 or Day 1 to Day 7) of drug free period. Therefore, this described administration regimen features an initial administration of the chemotherapeutic or immunotherapy agent or a combination of 2-3 agents, 2 weeks of tyrosine kinase inhibitor administration period and 7 days of tyrosine kinase inhibitor free period. The administration process repeats and follows the same regimen.

In some embodiments, the described periodic chemo combination therapy comprises at least 1-10 cycles of chemotherapy or immunotherapy agent(s), preferably 1-6 cycles of chemotherapy or immunotherapy agent(s). After the completion of 1-10 cycles of the chemo combination therapy, the tyrosine kinase inhibitor could be administrated individually without the utilization of chemotherapeutic nor immunotherapy agent(s) for maintenance therapy which can be used for 1-2 years, preferably 0.5-1 year.

In some embodiments, the described periodic chemo combination therapy comprises continuing treatment of chemotherapy or immunotherapy agent(s) with the tyrosine kinase inhibitor until patient intolerability or progression disease.

The tyrosine kinase inhibitor is AL3818 or its pharmaceutical acceptable salts, or its crystallines can be administrated, but not limited, at equal to or lower than 12 mg per day during chemo or immuno combination therapy period and equal to or lower than 16 mg per day during maintenance therapy period. Preferably 8 mg per day during chemo or immuno combination therapy period; and 8 mg, 10 mg or 12 mg per day during maintenance therapy period. In some special circumstances, the dosage strength of compound AL3818 or its pharmaceutical acceptable salts might be acceptable at 16 mg.

The dosage described at here was calculated according to the form of free base.

In a particular embodiment, the chemotherapeutic agents are the standard chemotherapy agents including gemcitabine, carboplatin, cisplatin, paclitaxel or carboplatin+paclitaxel and cisplatin+paclitaxel.

The described chemo or immuno combination therapy regimen can be applied for treating tumors including but not limited to ovarian cancer, endometrial cancer or cervical cancer.

In the embodiments of ovarian cancer or endometrial cancer, the chemotherapy agents are paclitaxel and carboplatin. In the embodiments of cervical cancer, the chemotherapy agents are paclitaxel and cisplatin. In the embodiments of platinum resistant ovarian cancer, the chemotherapy agent is selected from paclitaxel (weekly), pegylated liposomal doxorubicin (PLD) and topotecan.

In this described chemo combination therapy regimen, the tyrosine kinase inhibitor includes, but not limited to imatinib mesylate, sunitinib malate, erlotinib hydrochloride, dasatinib, lapatinib mesylate, nilotinib, gefitinib, and icotinib hydrochloride. In a particular embodiment, the tyrosine kinase inhibitor is compound AL3818 (anlotinib).

In some embodiments, the daily dosage of compound AL3818 is from 6 mg-16 mg which is calculated towards the content of free base. In more specific embodiments, the daily dosage of compound AL3818 is selected from 6 mg, 8 mg, 10 mg, 12 mg, 14 mg and 16 mg. The preferred daily dosage of compound AL3818 in the stage of chemo combination therapy is 8 mg. The preferred daily dosage of compound AL3818 in the stage of mono-therapy of maintenance period can be selected from 8 mg, 10 mg and 12 mg which follows two weeks on and one week off pattern. In some special scenarios, the compound AL3818 or its pharmaceutical acceptable salts might be bearable at a dosage of 16 mg.

The details for one or more embodiments of the invention are described in. Other necessary objects and features of this invention will be apparent from the description and from the claims.

This present invention provides a therapy regimen for treating cancer, which relates to administrate a daily dosage of compound AL3818 (anlotinib, INN: catequentinib) to patients.

The chemical name of AL3818 (anlotinib) is (1-[[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropaneamine, which features the following chemical structure:

The compound AL3818 (anlotinib) can be administrated to the patients in the form of free base. It can also be administrated in the form of salts, hydrates and prodrugs (will be converted into the free base form in vivo). In this described embodiments, AL3818 is administrated in the form of pharmaceutically acceptable salts.

The conception of “pharmaceutically acceptable salts” includes, but not limited to acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like; or acid addition salts formed from organic acids such as 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (−L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (−L), salicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), undecylenic acidand the like (see P. H. Stahl and C. G. Wermuth, editors,, Weinheim/Zürich: Wiley-VCH/VHCA, 2002.).

A preferred pharmaceutically acceptable salt of compound AL3818 is the hydrochloride salt. In this described embodiment, compound AL3818 (anlotinib) is administrated in the form of dihydrochloride salt. Another preferred pharmaceutically acceptable salt of compound AL3818 is the maleic acid salt. In this described embodiment, compound AL3818 is administrated in the form of dimaleic acid salt.

Compound AL3818 (anlotinib) or its pharmaceutically acceptable salts can be administrated to patients via various administration routes, and these routes include, but not limited to: orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via inhalation, vaginally, intraoccularly, via local administration, subcutaneously, intraadiposally, intraarticularly, intraperitoneally or intrathecally. In this described embodiment, the administration is performed orally.

The pharmaceutical compositions of compound AL3818 (anlotinib) or its pharmaceutically acceptable salts suitable for oral administration include, but not limited to tablets, capsules, dusts, granulates, drip pills, pastes, powders and tinctures. Tablets and capsules are the preferred pharmaceutical compositions among them. In a certain embodiment, capsules are the more preferred pharmaceutical compositions.

The present invention provides a therapy regimen for treating cancer, which comprises administrating a daily orally dosage of 6-16 mg compound AL3818 (anlotinib) or its pharmaceutically acceptable salts to patients. In an embodiment, compound AL3818 (anlotinib) is administrated in the form of pharmaceutically acceptable salts to the patient. In a further embodiment, compound AL3818 (anlotinib) is administrated in the form of dihydrochloride salt to patients. In yet a further embodiment, compound AL3818 (anlotinib) is administrated in the form of dihydrochloride salt in capsules to patients. The daily orally dosage of compound AL3818 dihydrochloride salt includes, but not limited to 6 mg, 8 mg, 10 mg, 12 mg, 14 mg and 16 mg which was calculated towards the content of free base. Another preferred pharmaceutically acceptable salt of compound AL3818 is the maleic acid salt. The dimaleic acid salt of compound AL3818 is administrated to the patient with or without pharmaceutical excipients. It is preferred with pharmaceutical excipients to be used as a capsule.

“Patients” refer to mammal, preferably human.

To meet the existing need, the present invention provides a chemo combination therapy regimen for treating cancer, which comprises an interval and sequential administration of compound AL3818 (anlotinib) or its pharmaceutically acceptable salts in combination with standard platinum-based chemotherapy or immunotherapy to patients.

In the standard chemotherapy or immunotherapy, 21 days is preferably been selected as one treatment cycle. This presented chemo combination therapy regimen takes the advantage of the 21-day cycle and intervally administrates the compound AL3818 (anlotinib) or its pharmaceutically acceptable salts to patients in the rest period.

As a kind of novel multi-target receptor tyrosine kinase inhibitor, compound AL3818 or its pharmaceutically acceptable salts could suppress the abnormal hyperactivity of protein tyrosine kinases (PTKs) in cancer cells. This action could inhibit the angiogenesis process of metastatic cancers, thus inhibit the development, invasion, and metastasis of tumors in the therapy free period of the standard chemotherapy or immunotherapy.

A Phase 1 trial was designed to determine the recommended phase 2 dose (RP2D) for part 2 (phase 2a) of the study. Aside of this, this trial was also designed to investigate the safety and tolerability of adding oral AL3818 dihydrochloride to standard platinum-based chemotherapy (carboplatin and paclitaxel) in patients via evaluation of dose limiting toxicity (DLT) events.

Patients in this trial were females with recurrent or advanced endometrial, ovarian, and cervical cancer.

In this presented chemo combination therapy regimen, in the first day of the 21-day cycle, standard platinum-based chemotherapeutic agents were administrated intravenously to the patients. In the embodiments of endometrial or ovarian or cervical cancer, paclitaxel (175 mg/minfusion over 3 hours) and carboplatin (AUC 5/6 according to local standard over approximately 30 minutes) were selected as chemotherapeutic agents. In the embodiment of cervical cancer, cisplatin (at a recommended dose of 75 mg/m) could be used instead of carboplatin. The weekly paclitaxel was used as SOC (standard of care) treatment for platinum resistant ovarian patients. 1-6 cycles of chemotherapy were applied for each individual patient.

Overall, in the presented chemo combination therapy regimen, compound AL3818 dihydrochloride capsules were administrated orally to the patients in a 14 days on and 7 days off pattern each cycle. After the intravenous (IV) chemotherapy on the Day 1, Day 2 to Day 7 was the therapy free period. From the first day of second week (Day 8), compound AL3818 (anlotinib) dihydrochloride capsules are administrated orally once daily to the patients for two weeks continuously until the end of the first 21-day cycle (Day 8 to Day 21).

From Day 22 (C2D1) (CXDY is the abbreviation for Cycle X Day Y. For example, C2D1 represents Cycle 2 Day 1), a new cycle began, paclitaxel and carboplatin (or cisplatin for cervical cancer) were administrated to the patients and Day 23 to Day 28 (C2D2

The first 21-day cycle plus 7 days (C1D1-CD8 or Day 1 to Day28) was crucial in this regimen and it was called the primary safety evaluation period. The recommended phase 2 dose (RP2D) was obtained by evaluating according to the standard for the dose limiting toxicity (DLT) events of patients in this period of time.

This evaluation period could be extended to the end of second cycle for the patients who passed the primary safety evaluation period. From Day 29 (C2D9), compound AL3818 (anlotinib) dihydrochloride capsules were administrated orally to the patients again for two weeks until Day 42 (C2D21). After the beginning of cycle 3 (C3D1), the patients had the option to continue on chemotherapy plus AL3818 for up to 6 cycles, then AL3818 dihydrochloride in mono therapy as maintenance for up to 12 months in total. During any time of the entire study, investigations were required to see if there showed clinical benefit, no disease progression, and the tolerability after the drug administration.

In this embodiment, if any serious dose limiting toxicity (DLT) events or other serious side effects occurred, according to the serious level, the patients might require to withdraw the treatment, reduce the dose of medication or switch to other medications.

A total of nine patients were enrolled in this study and the compound AL3818 dihydrochloride dosage strength was selected from 12 mg, 10 mg and 8 mg (calculated according to the form of free base). As a result, three patients were assigned into each group, accordingly.

In the first group (12 mg AL3818 dihydrochloride), two of the patients out of three observed dose limiting toxicity (DLT) events during the primary safety evaluation period. As a result of this, one of the patients had to permanently discharge from this study and the other one selected to lower the dosage to 10 mg and continued for another two cycles. The only patient did not face dose limiting toxicity (DLT) event also selected to reduce the dosage of compound AL3818 to 10 mg on C3D1 due to intolerable chemotherapy side effects.

In the second group (10 mg AL3818 dihydrochloride), one of the patients faced dose limiting toxicity (DLT) event after receiving paclitaxel chemotherapy and 8 doses of AL3818 in the first cycle (C1D16) and the study on this patient was permanent discontinued. The other two patients in this group successfully passed the primary safety evaluation period, but shows some non-serious side effects (did not qualify DLT event standard). Due to this reason, the dosage of AL3818 was reduced to 8 mg for these two patients so that the study could go proceed.